A review on increasing risk for gastrointestinal bleeding associated with dabigatran

Dabigatran, a reversible direct thrombin inhibitor, is widely used in clinical practice as a therapeutic option due to its unique mechanism of action in comparison to other anticoagulants. Although patients taking dabigatran experience a reduced risk of fatal bleeding, a higher risk of gastrointestinal bleeding (GIB) is associated with dabigatran, and its rational use between anticoagulation and bleeding is challenging for clinicians. To prevent GIB, it is imperative for clinicians to understand the pharmacological characteristics of dabigatran to ensure that its prescription should be avoided in patients with bleeding. In this review, we summarize the mechanism of action and pharmacokinetics of dabigatran and bleeding sites in the gastrointestinal tract in patients treated with dabigatran, as well as discuss the factors that increase the risk of dabigatran-induced GIB, including dose, age, drug interactions, race, genetics and past medical history. Finally, the treatment and prevention of GIB with dabigatran is also discussed. This review will help clinicians choose their drugs and doses more carefully for treating GIB.

Dabigatran; Gastrointestinal bleeding; Risk factors; Treatment

[1] Botto GL, Ameri P, De Caterina R. Many good reasons to switch from vitamin K antagonists to non-vitamin K antagonists in patients with non-valvular atrial fibrillation. Journal of Clinical Medicine. 2021; 10: 2866.

[2] Wei S, Sawhney A, Khandait H, Meda A, Gupta V, Jain R. An update on applications and limitations of direct oral anticoagulants. The Egyptian Journal of Internal Medicine. 2023; 35: 26.

[3] Singh B, Pai P, Kumar H, George S, Mahapatra S, Garg V, et al. Expert recommendations on the usage of nonvitamin K antagonist oral anticoagulants (NOACs) from India: current perspective and future direction. Cardiol Therapeutics. 2022; 11: 49–79.

[4] Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. EP Europace. 2021; 23: 1612–1676.

[5] Tun HN, Kyaw MT, Rafflenbeul E, Suástegui XL. Role of direct oral anticoagulants for post-operative venous thromboembolism prophylaxis. European Society of Cardiology. 2022; 17: e11.

[6] Su X, Wei Y, Pang S, Zhang Z, Zhang Y, Zheng P, et al. Clinical characteristics and risk factors of in-hospital mortality in patients with acute myocardial infarction with subsequent gastrointestinal bleeding: a single-center experience. Frontiers in Cardiovascular Medicine. 2022; 9: 942467.

[7] Yanagisawa D, Abe K, Amano H, Komatsuda S, Honda T, Manabe D, et al. Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants for non-valvular atrial fibrillation. PLOS ONE. 2021; 16: e0260585.

[8] Gu ZC, Wei AH, Zhang C, Wang XH, Zhang L, Shen L, et al. Risk of major gastrointestinal bleeding with new vs conventional oral anticoagulants: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2020; 18: 792–799.e61.

[9] Carmo J, Moscoso Costa F, Ferreira J, Mendes M. Dabigatran in real-world atrial fibrillation. Meta-analysis of observational comparison studies with vitamin K antagonists. Journal of Thrombosis and Haemostasis. 2016; 116: 754–763.

[10] Zappulla P, Calvi V. Gastrointestinal bleeding and direct oral anticoagulants among patients with atrial fibrillation: risk, prevention, management, and quality of life. TH Open. 2021; 05: e200–e210.

[11] Smeda M, Stojak M, Przyborowski K, Sternak M, Suraj-Prazmowska J, Kus K, et al. Direct thrombin inhibitor dabigatran compromises pulmonary endothelial integrity in a murine model of breast cancer metastasis to the lungs; the role of platelets and inflammation-associated haemostasis. Frontiers in Pharmacology. 2022; 13: 834472.

[12] Yin L, Qi Y, Ge Z, Li J. Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits. Open Life Sciences. 2022; 17: 1–9.

[13] Samama MM. The mechanism of action of rivaroxaban—an oral, direct Factor Xa inhibitor—compared with other anticoagulants. Thrombosis Research. 2011; 127: 497–504.

[14] Ng JW, Mohd Tahir NA, Chin PKL, Makmor‐Bakry M, Mohd Saffian S. A systematic review and meta-analysis of dabigatran peak and trough concentration in adults. British Journal of Clinical Pharmacology. 2022; 88: 4443–4459.

[15] Carnicelli AP, Hong H, Connolly SJ, Eikelboom J, Giugliano RP, Morrow DA, et al. Direct oral anticoagulants versus warfarin in patients with atrial fibrillation: patient-level network meta-analyses of randomized clinical trials with interaction testing by age and sex. Circulation. 2022; 145: 242–255.

[16] Oi K, Shimizu M, Natori T, Tsuda K, Yoshida M, Kamada A, et al. Influence of PAR-1 in patients with non-valvular atrial fibrillation: the antiplatelet effect of dabigatran. Thrombosis Research. 2021; 201: 123–130.

[17] Pesei ZG, Jancsó Z, Demcsák A, Németh BC, Vajda S, Sahin-Tóth M. Preclinical testing of dabigatran in trypsin-dependent pancreatitis. JCI Insight. 2022; 7: e161145.

[18] Grześk G, Rogowicz D, Wołowiec Ł, Ratajczak A, Gilewski W, Chudzińska M, et al. The clinical significance of drug-food interactions of direct oral anticoagulants. International Journal of Molecular Sciences. 2021; 22: 8531.

[19] Sherid M, Sifuentes H, Sulaiman S, Samo S, Husein H, Tupper R, et al. Risk of gastrointestinal bleeding with dabigatran: a head-to-head comparative study with rivaroxaban. Digestion. 2014; 90: 137–146.

[20] Lin S, Wang Y, Zhang L, Guan W. Dabigatran must be used carefully: literature review and recommendations for management of adverse events. Drug Design, Development and Therapy. 2019; 13: 1527–1533.

[21] Vidal J, DePalma R, Forouzan L. Reversal of dabigatran bleeding and coagulopathy using idarucizumab in a patient with acute kidney injury. Pharmacy and Therapeutics. 2018; 43: 748–749.

[22] Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clinical Pharmacokinetics. 2008; 47: 285–295.

[23] Moner-Banet T, Alberio L, Bart PA. Does one dose truly fit all? On the monitoring of direct oral anticoagulants: a review of the literature. Hamostaseologie. 2020; 40: 184–200.

[24] Derebail VK, Rheault MN, Kerlin BA. Role of direct oral anticoagulants in patients with kidney disease. Kidney International. 2020; 97: 664–675.

[25] Skripka A, Sychev D, Bochkov P, Shevchenko R, Krupenin P, Kogay V, et al. Factors affecting trough plasma dabigatran concentrations in patients with atrial fibrillation and chronic kidney disease. High Blood Pressure & Cardiovascular Prevention. 2020; 27: 151–156.

[26] Saviano A, Brigida M, Petruzziello C, Candelli M, Gabrielli M, Ojetti V. Gastrointestinal bleeding due to NOACs use: exploring the molecular mechanisms. International Journal of Molecular Sciences. 2022; 23: 13955.

[27] Wieland E, Shipkova M. Pharmacokinetic and pharmacodynamic drug monitoring of direct-acting oral anticoagulants: where do we stand? Therapeutic Drug Monitoring. 2019; 41: 180–191.

[28] Chan KE, Giugliano RP, Patel MR, Abramson S, Jardine M, Zhao S, et al. Nonvitamin K anticoagulant agents in patients with advanced chronic kidney disease or on dialysis with AF. Journal of the American College of Cardiology. 2016; 67: 2888–2899.

[29] Schnee J, Fraeman K, Siu K, Reynolds MW, Collins J, Schwartzman E, et al. A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system. Thrombosis and Haemostasis. 2015; 114: 1290–1298.

[30] Sherid M, Sifuentes H, Sulaiman S, Samo S, Husein H, Tupper R, et al. Gastrointestinal bleeding with dabigatran, a comparative study with warfarin: a multicenter experience. The Korean Journal of Gastroenterology. 2015; 65: 205–214.

[31] Kolb JM, Flack KF, Chatterjee-Murphy P, Desai J, Wallentin LC, Ezekowitz M, et al. Locations and mucosal lesions responsible for major gastrointestinal bleeding in patients on warfarin or dabigatran. Digestive Diseases and Sciences. 2018; 63: 1878–1889.

[32] Di Minno MND, Ambrosino P, Di Minno A, Tremoli E, Di Minno G. The risk of gastrointestinal bleeding in patients receiving dabigatran etexilate: a systematic review and meta-analysis of the literature. Annals of Medicine. 2017; 49: 329–342.

[33] Tsivgoulis G, Krogias C, Sands KA, Sharma VK, Katsanos AH, Vadikolias K, et al. Dabigatran etexilate for secondary stroke prevention: the first year experience from a multicenter short-term registry. Therapeutic Advances in Neurological Disorders. 2014; 7: 155–161.

[34] Bolek T, Samoš M, Škorňová I, Galajda P, Staško J, Kubisz P, et al. Proton pump inhibitors and dabigatran therapy: impact on gastric bleeding and dabigatran plasma levels. Seminars in Thrombosis and Hemostasis. 2019; 45: 846–850.

[35] Abraham NS, Singh S, Alexander GC, Heien H, Haas LR, Crown W, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. The BMJ. 2015; 350: h1857.

[36] Chan EW, Lau WC, Leung WK, Mok MT, He Y, Tong TS, et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology. 2015; 149: 586–595.e3.

[37] Maruyama K, Yamamoto T, Aoyagi H, Isono A, Abe K, Kodashima S, et al. Difference between the upper and the lower gastrointestinal bleeding in patients taking nonvitamin K oral anticoagulants. BioMed Research International. 2018; 2018: 7123607.

[38] Romanelli RJ, Nolting L, Dolginsky M, Kym E, Orrico KB. Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice. Circulation: Cardiovascular Quality and Outcomes. 2016; 9: 126–134.

[39] Avgil-Tsadok M, Jackevicius C, Essebag V, Eisenberg MJ, Rahme E, Behlouli H, et al. Dabigatran use in elderly patients with atrial fibrillation. Thrombosis and Haemostasis. 2016; 115: 152–160.

[40] Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, et al. Cardiovascular, Bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015; 131: 157–164.

[41] Ezekowitz MD, Wallentin L, Connolly SJ, Parekh A, Chernick MR, Pogue J, et al. Dabigatran and warfarin in vitamin K antagonist–naive and –experienced cohorts with atrial fibrillation. Circulation. 2010; 122: 2246–2253.

[42] Yavuz B, Ayturk M, Ozkan S, Ozturk M, Topaloglu C, Aksoy H, et al. A real world data of dabigatran etexilate: multicenter registry of oral anticoagulants in nonvalvular atrial fibrillation. Journal of Thrombosis and Thrombolysis. 2016; 42: 399–404.

[43] He Y, Wong IC, Li X, Anand S, Leung WK, Siu CW, et al. The association between non-vitamin K antagonist oral anticoagulants and gastrointestinal bleeding: a meta-analysis of observational studies. British Journal of Clinical Pharmacology. 2016; 82: 285–300.

[44] Bouget J, Viglino D, Yvetot Q, Oger E. Major gastrointestinal bleeding and antithrombotics: characteristics and management. World Journal of Gastroenterology. 2020; 26: 5463–5473.

[45] Chan EW, Lau WC, Leung WK, Mok MT, He Y, Tong TS, et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology. 2015; 149: 586–595.e3.

[46] Ray WA, Chung CP, Murray KT, Smalley WE, Daugherty JR, Dupont WD, et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA. 2018; 320: 2221–2230.

[47] Wang M, Paterson M, Thabane L, Siegal D, Mbuagbaw L, Targownik L, et al. Association of direct oral anticoagulant-proton pump inhibitor cotherapy with adverse outcomes: protocol for a population-based cohort study. BMJ Open. 2022; 12: e057991.

[48] Ferri N, Colombo E, Tenconi M, Baldessin L, Corsini A. Drug‒drug interactions of direct oral anticoagulants (DOACs): from pharmacological to clinical practice. Pharmaceutics. 2022; 14: 1120.

[49] Pham P, Schmidt S, Lesko L, Lip GYH, Brown JD. Association of oral anticoagulants and verapamil or diltiazem with adverse bleeding events in patients with nonvalvular atrial fibrillation and normal kidney function. JAMA Network Open. 2020; 3: e203593.

[50] Naccarelli GV, Wolbrette DL, Levin V, Samii S, Banchs JE, Penny-Peterson E, et al. Safety and efficacy of dronedarone in the treatment of atrial fibrillation/flutter. Clinical Medicine Insights: Cardiology. 2011; 5: 103–119.

[51] Gandhi SK, Reiffel JA, Boiron R, Wieloch M. Risk of major bleeding in patients with atrial fibrillation taking dronedarone in combination with a direct acting oral anticoagulant (from a U.S. claims database). The American Journal of Cardiology. 2021; 159: 79–86.

[52] Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, et al. Association between use of non–vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA. 2017; 318: 1250–1259.

[53] Chang KH, Chen CM, Wang CL, Tu HT, Huang YT, Wu HC, et al. Major bleeding risk in patients with nonvalvular atrial fibrillation concurrently taking direct oral anticoagulants and antidepressants. Frontiers in Aging Neuroscience. 2022; 14: 791285.

[54] Antoniou T, Macdonald EM, Yao Z, Hollands S, Gomes T, Tadrous M, et al. Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation. Canadian Medical Association Journal. 2017; 189: E4–E10.

[55] Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z, et al. Risk of hospitalization with hemorrhage among older adults taking clarithromycin vs azithromycin and direct oral anticoagulants. JAMA Internal Medicine. 2020; 180: 1052–1060.

[56] Kanuri SH, Kreutz RP. Pharmacogenomics of novel direct oral anticoagulants: newly identified genes and genetic variants. Journal of Personalized Medicine. 2019; 9: 7.

[57] Shnayder NA, Petrova MM, Shesternya PA, Savinova AV, Bochanova EN, Zimnitskaya OV, et al. Using pharmacogenetics of direct oral anticoagulants to predict changes in their pharmacokinetics and the risk of adverse drug reactions. Biomedicines. 2021; 9: 451.

[58] Ross S, Paré G. Pharmacogenetics of antiplatelets and anticoagulants: a report on clopidogrel, warfarin and dabigatran. Pharmacogenomics. 2013; 14: 1565–1572.

[59] Dimatteo C, D’Andrea G, Vecchione G, Paoletti O, Cappucci F, Tiscia GL, et al. Pharmacogenetics of dabigatran etexilate interindividual variability. Thrombosis Research. 2016; 144: 1–5.

[60] Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. EP Europace. 2015; 17: 1467–1507.

[61] Aulinger BA, Saner FH, Stark K, Mayerle J, Lange CM. Platelet aggregation inhibitors and anticoagulants in gastroenterological and visceral surgical procedures. Deutsches Arzteblatt International. 2022; 119: 851–860.

[62] Kam W, Holmes DN, Hernandez AF, Saver JL, Fonarow GC, Smith EE, et al. Association of recent use of non-vitamin K antagonist oral anticoagulants with intracranial hemorrhage among patients with acute ischemic stroke treated with alteplase. JAMA. 2022; 327: 760–771.

[63] Lau JYW. Management of acute upper gastrointestinal bleeding: urgent versus early endoscopy. Digestive Endoscopy. 2022; 34: 260–264.

[64] Cañamares-Orbís P, Lanas Arbeloa Á. New trends and advances in non-variceal gastrointestinal bleeding—series II. Journal of Clinical Medicine. 2021; 10: 3045.

[65] Carballo F, Albillos A, Llamas P, Orive A, Redondo-Cerezo E, Rodríguez de Santiago E, et al. Consensus document of the Spanish society of digestives diseases and the Spanish society of thrombosis and haemostasis on massive nonvariceal gastrointestinal bleeding and direct-acting oral anticoagulants. Revista Espanola De Enfermedades Digestivas. 2022; 114: 375–389.

[66] Zappulla P, Calvi V. Gastrointestinal bleeding and direct oral anticoagulants among patients with atrial fibrillation: risk, prevention, management, and quality of life. TH Open. 2021; 5: e200–e210.

[67] Haastrup SB, Hellfritzsch M, Nybo M, Hvas AM, Grove EL. Real-world experience with reversal of dabigatran by idarucizumab. Thrombosis Research. 2021; 197: 179–184.

[68] van der Horst SFB, Martens ESL, den Exter PL, Bos MHA, van Mens TE, Huisman MV, et al. Idarucizumab for dabigatran reversal: a systematic review and meta-analysis of indications and outcomes. Thrombosis Research. 2023; 228: 21–32.